CE-158

{{Short description|Chemical compound}}

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| class = Atypical dopamine reuptake inhibitor

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| CAS_number = 2621388-55-2

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| PubChem = 156150588

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| synonyms = (S,S)-CE-158; S,S-CE-158

| IUPAC_name = 5-(3-bromophenyl)-phenylmethyl sulfinylmethyl-1,3-thiazole

| C=17 | H=14 | Br=1 | N=1 | O=1 | S=2

| SMILES = C1=CC=C(C=C1)C(C2=CC(=CC=C2)Br)S(=O)CC3=CN=CS3

| StdInChI = 1S/C17H14BrNOS2/c18-15-8-4-7-14(9-15)17(13-5-2-1-3-6-13)22(20)11-16-10-19-12-21-16/h1-10,12,17H,11H2

| StdInChIKey = KWWHBBCVAQTAFQ-UHFFFAOYSA-N

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CE-158 is an atypical dopamine reuptake inhibitor (DRI) that was derived from modafinil.{{cite journal | vauthors = Salamone JD, Correa M | title = The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine | journal = Annu Rev Psychol | volume = 75 | issue = 1| pages = 1–32 | date = January 2024 | pmid = 37788571 | doi = 10.1146/annurev-psych-020223-012208 | url = | quote = Several atypical DAT inhibitors have been successful at reversing the effects of TBZ at doses that increase extracellular DA as measured by microdialysis, including CT-005404 (Rotolo et al. 2021), and the modafinil analogs CE-123 (Rotolo et al. 2019), CE-158 (Rotolo et al. 2020), and MK-26 (Kouhnavardi et al. 2022). [...] Furthermore, several drugs that inhibit DAT, when administered on their own, increase selection of high-effort PROG lever pressing in rats tested on the PROG/chow choice task, including bupropion (Randall et al. 2015); lisdexamfetamine (Yohn et al. 2016e); PRX-14040 (Yohn et al. 2016d); GBR 12909 (Yohn et al. 2016c); CE-123, CE-158, and CT-5404 (Rotolo et al. 2019, 2020, 2021); and MK-26 (Kouhnavardi et al. 2022).| hdl = 10234/207207 | hdl-access = free }}{{cite book | vauthors = Treadway MT, Salamone JD | title = Anhedonia: Preclinical, Translational, and Clinical Integration | chapter = Vigor, Effort-Related Aspects of Motivation and Anhedonia | series = Current Topics in Behavioral Neurosciences | volume = 58 | issue = | pages = 325–353 | date = 2022 | location = Cham | pmid = 35505057 | doi = 10.1007/7854_2022_355 | isbn = 978-3-031-09682-2 | chapter-url = | quote = Recent papers have assessed the effort-related effects of the novel atypical DAT inhibitors (S)-CE-123, (S,S)-CE158, and CT-005404. All three compounds reversed the low-effort bias induced by [tetrabenazine (TBZ)], and also increased selection of high-effort PROG lever pressing while decreasing chow intake (Rotolo et al. 2019, 2020, 2021). These compounds also produced modest but significant increases in extracellular DA in nucleus accumbens core, [...] atypical DAT inhibitors offer promise as potential treatments for effort-related motivational symptoms.}}{{cite journal | vauthors = Hersey M, Bartole MK, Jones CS, Newman AH, Tanda G | title = Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors | journal = Molecules | volume = 28 | issue = 13 | date = July 2023 | page = 5270 | pmid = 37446929 | pmc = 10343811 | doi = 10.3390/molecules28135270 | doi-access = free | url = | quote = S,S-CE-158, a highly DAT-selective and atypical DAT inhibitor, demonstrated an ability to stabilize recognition memory during the information acquisition process in a dose-dependent manner in mice [193]. S,S-CE-158 induced a substantial and sustained increase in mice extracellular nucleus accumbens DA [193,194] but showed no significant effect on locomotor activity following acute or repeated exposure [194]. In addition, S,S-CE-158 attenuated the dopaminergic releasing effects of amphetamine in cells stably expressing hDAT and enhanced learning acquisition responses and neuronal activity in rats [194]. Furthermore, it was recently reported that only a high dose (20 mg/kg) of S,S-CE-158 increased locomotor activity in mice, and that a subthreshold dose (10 mg/kg) rescued motor learning deficits propagated by dopaminergic mGluR5 silencing, suggesting a role in DAT trafficking [195]. Therefore, understanding the effects of S,S-CE-158 in both males and females in animal models of PSUD will be very interesting.}}{{cite journal | vauthors = Shaikh A, Ahmad F, Teoh SL, Kumar J, Yahaya MF | title = Targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease | journal = Front Cell Neurosci | volume = 17 | issue = | pages = 1292858 | date = 2023 | pmid = 38026688 | pmc = 10679733 | doi = 10.3389/fncel.2023.1292858 | doi-access = free | url = | quote = Due to their high DAT specificity, synthetic modafinil analogs like R-modafinil, S-CE-123 (S-5-((benzhydrylsulfinyl)methyl) thiazole), S,S-CE158 (5-(((S)-((S)-(3-bromophenyl)(phenyl) methyl)sulfinyl)methyl)thiazole), and S-MK-26 ((S)-5-(((B(3- chlorophenyl)methyl)sulphinyl)methyl)thiazole) do not exert any effect on the reward pathway, making them less likely to cause addiction, abuse or withdrawal symptoms compared to the parent drug and other non-specific counterparts (Kristofova et al., 2018; Sagheddu et al., 2020; Hazani et al., 2022; Kouhnavardi et al., 2022).}}{{cite journal | vauthors = Rotolo RA, Kalaba P, Dragacevic V, Presby RE, Neri J, Robertson E, Yang JH, Correa M, Bakulev V, Volkova NN, Pifl C, Lubec G, Salamone JD | title = Behavioral and dopamine transporter binding properties of the modafinil analog (S, S)-CE-158: reversal of the motivational effects of tetrabenazine and enhancement of progressive ratio responding | journal = Psychopharmacology (Berl) | volume = 237 | issue = 11 | pages = 3459–3470 | date = November 2020 | pmid = 32770257 | pmc = 7572767 | doi = 10.1007/s00213-020-05625-6 | url = }} It is often but not always referred to as the enantiopure enantiomer (S,S)-CE-158 instead.

CE-158 is a highly selective DRI with much greater potency than modafinil. As (S,S)-CE-158, its inhibitory potencies ({{Abbrlink|IC₅₀|half-maximal inhibitory concentration}}) at the monoamine transporters are 227{{nbsp}}nM at the dopamine transporter (DAT), 11,970{{nbsp}}nM at the norepinephrine transporter (NET) (53-fold lower), and inactive at the serotonin transporter (SERT).

The drug shows pro-motivational effects in animals and reverses tetrabenazine-induced motivational deficits. It increases dopamine levels in the nucleus accumbens, blocks amphetamine-induced dopamine release in vitro, shows no effect on locomotor activity with acute or repeated administration except at a high dose, and enhances learning in animals.

CE-158 was first described by 2020. It is closely related to CE-123, an earlier modafinil analogue. CE-158 and related agents are of interest in the potential treatment of motivational disorders, psychostimulant use disorder (PSUD), and Alzheimer's disease.